The use of isometric as compared to rhythmic exercise in the general field of athletic strength development, as well as a therapy for strength recovery has been the subject of somewhat controversial discourse over the past decades. In general, such exercise has been considered to promote, for example, coronary risk factors. See generally:                (1) Vecht R J, Graham G W S, Sever P S. “Plasma Noradrenaline Concentrations During Isometric Exercise.” Brit Heart J. 1978;40:1216-20.        (2) Chrysant S G. “Hemodynamic Effects of Isometric Exercise in Normotensive Hypertensive Subjects”: Hypertension. Angiology 1978:29(5):379-85.        
However, as such attitudes persisted, some investigators commenced to observe contradictions to these generally accepted beliefs. See for, example, the following publications:                (3) Buck, et al., “Isometric Occupational Exercise and the Incidence of Hypertension”, J. Occup. Med., 27:370-372, 1985        (4) Choquette. et al., “Blood Pressure Reduction in ‘Borderline’ Hypertensives Following Physical Training” Can. Med. Assoc. J. 1108:699-703, 1973.        (5) Clark, et al., “The Duration of Sustained Contractions of the Human Forearm of Different Muscle Temperatures”, J. Physiol., 143:454-473, 1958.        (6) Gilders, et al., “Endurance Training and Blood Pressure in Normotensive and Hypertensive Adults”, Med. Sci. Sports Exerc. 21:629-636, 1989.        (7) Hagberg, et al., “Effect of Weight Training on Blood Pressure and Hemodynamics in Hypertensive Adolescents”, J. Pediatr. 1104:147-151, 1984.        (8) Harris, et al., “Physiological Response to Circuit Weight Training in Borderline Hypertensive Subjects”, Med. Sci. Sports Exerc., 19:246-252, 1987.        (9) Hurley, et al., “Resistive Training Can Induce Coronary Risk Factors Without Altering Vo2 max or Percent Body Fat” Med. Sci. Sports Exerc. 20:150-154, 1988.        (10) Hypertension Detection and Follow-up Program Cooperative Group, “The Effect of Treatment on Mortality in ‘Mild’ Hypertension”, N. Engl. J. Med., 307:976-980, 1982.        (11) Kiveloff, et al., “Brief Maximal Isometric Exercise in Hypertension”, J. Am. Geriatr. Soc., 9:1006-1012, 1971.        (12) Merideth et al., “Exercise Training Lowers Resting Renal but not Cardiac Sympathetic Activity n Humans”, Hypertension, 18:575-582, 1991.        (13) Seals and Hagberg, “The Effect of Exercise Training on Human Hypertension: A Review”, Med. Sci. Sports Exerc. 16:207-215, 1984.        (14) Hanson P. Nagle F. “Isometric Exercise: Cardiovascular Responses in Normal and Cardiac Populations.” Cardiology Clinics 1987; 5(2): 157-70.Such speculation on the part of these early observers was confirmed by Wiley in the 1990s, as described in U.S. Pat. No. 5,398,696 entitled “Isometric Exercise Method for Lowering Resting Blood Pressure and Grip Dynamometer Useful Therefore”, issued Mar. 21, 1995 and as described in the following publication:        (15) Wiley, et al., “Isometric Exercise Training Lowers Resting Blood Pressure”, Med. Sci. Sports Exerc. 29:749-754, 1992.        
With the approach of protocol developed by Wiley, the isometric regimen is closely controlled both in terms of exerted force and in the timing of trials or exertions. The system and method described by Wiley are known to be useful for treating hypertension. Hypertension is associated with an increased risk of a wide range of disease and disorder, including stroke, organ failure, and particularly cardiopathy. The exact causes of hypertension are rarely known with certainty, but risk factors for hypertension include obesity, genetic factors, smoking, diet and inactivity. As Wiley has shown, not all forms of exercise provide equivalent therapeutic benefit to the cardiovascular system and for the treatment of hypercholesterolemia, with a protocol for brief maximal isometric exercise providing a clear benefit.
Hypertension, hypercholesterolemia, atherosclerosis and cardiovascular disease hare interrelated in their causes, treatment and effect on the body. The class of drugs known as HMG-CoA reductase inhibitors or statins is widely prescribed for treatment of hypercholesterolemia and associated cardiovascular disease, including the debilitating effects of progressive atherosclerosis. Various statins that have been clinically utilized include atovastatin, cerivastatin, fluvastatin, ovastatin simvastatin among others. The statin drugs were initially prescribed to relieve hypercholesterolemia, and to reduce the blood concentrations of low-density lipoprotein (LDL) and triglycerides. It has become apparent that the statin drugs apparently have additional therapeutic benefits that are independent and or interrelated with the effects of reduction in blood cholesterol concentration. The effect of statin drugs thus includes a reduction in vascular inflammation, and a protection of the heart against ischemic disorders. For more information on the pleiotropic effects of the statin drugs see generally:                (16) Davignon J., “Beneficial cardiovascular pleiotropic effects of statins.” Circulation. 109 (23 Suppl 1):III39-43 (2004).        (17) Elrod J W, Lefer D J The effects of statins on endothelium, inflammation and cardioprotection. Drug News Perspect. 18(4):229-36 (2005, May).        (18) Assanasen C, et al., Cholesterol binding, efflux, and a PDZ-interacting domain of scavenger receptor-BI mediate HDL-initiated signaling. J Clin Invest. 115(4):969-77 (2005 April).        
Although the exact mechanism of statin drug action for cardioprotection is not fully known, it is widely believed that statin drugs stimulate nitric oxide synthase activity in vascular endothelium, and presumably in other tissues. Disorders of the vascular endothelium related to in nitric oxide metabolism are believed to play a crucial role in the pathogenesis of atherosclerosis in hypercholesterolemia. Thus, certain cardioprotective effects of statin drugs can be mimicked in part by other physiological stimuli that induce nitric oxide synthase and increase nitric oxide availability. Moreover, nitric oxide metabolism is interconnected with the metabolism and regulation of LDL, cholesterol and triglycerides, and with the progress of atherosclerosis. As one example of this interrelationship, changes in nitric oxide levels have been inversely correlated with changes in LDL-cholesterol concentrations.
Nitric oxide (NO) has been identified as a signaling molecule in mammalian and other systems. NO, is a labile, endogenously produced gas that is enzymatically synthesized, can rapidly diffuse, and quickly disappear. NO is known to be a potent regulator of blood pressure due to its activity as a vasodilator, but has a diverse action on a wide variety of organ systems. Endothelial nitric oxide synthase (eNOS) is induced to synthesize NO by blood vessel wall shear stress. Upon the activation of eNOS and induction of NO synthesis, NO is released by endothelial cells. Based on the position of endothelial cells lining the inner surface of blood vessels, NO can be released into the blood stream, where it can act both locally and systemically. NO induces vasodilation by a reduction in the contraction of smooth muscle cells lining blood vessels. NO acts as a negative feedback for mean arterial pressure, since as arterial pressure increases, wall shear stress increases, inducing eNOS and increasing the NO concentration. As NO concentration increases, smooth muscle contraction is decreased, blood vessel lumen diameter increases, arteriole resistance decreases and arterial pressure decreases. The modulating action of wall shear stress on eNOS activity and NO production serves to maintain wall shear stress at a constant level. A diagram highlighting some of the interactions between NO, local metabolites, wall shear stress and smooth muscle contraction is shown in FIG. 20.
Prolonged elevation of wall shear stress, in addition to activation of eNOS, leads to the transcriptional activation of the eNOS gene in endothelial cells. After several hours, eNOS enzyme levels increase due to the induced transcription of the eNOS gene. Increased levels of eNOS enzyme in endothelial cells increases those cells ability to release NO following induction of eNOS activity. It is thus expected that those cells which have experienced prolonged elevation of wall shear stress will have an increased ability to synthesize NO, and the same levels of wall shear stress will result in a greater synthesis of NO. One effect of increased eNOS levels is a reduction in the amount of wall shear stress that is required to induce biologically significant NO levels. Blood vessels that have been entrained by prolonged elevation of wall shear stress will release more NO relative to shear stress, and the vasodilation effect of NO will be increased, Higher relative NO concentration leads to reduced smooth muscle contraction, increased blood vessel lumen diameter and decreased arteriole resistance. Assuming that the cardiac output of the heart does not change, the net effect of a lower “set point” for responding to wall shear stress is a reduction in total peripheral resistance in blood vessels and a reduction in mean arterial pressure.
Similar to the effects of the statin drugs, an improvement in endothelial function is interconnected with LDL and cholesterol blood levels and NO bioavailability. LDL and cholesterol have been shown to prevent the down-regulation of eNOS. In turn, down-regulation of eNOS is apparently mediated by the stimulation of levels of caveolin-1 by LDL. Caveolin-1 is an important inhibitor of eNOS catalytic activity. Modulation of NO is expected to affect the interrelated blood lipid concentrations of VHDL, HDL, LDL, and cholesterol. To the extent that the pleiotropic activity of the cholesterol lowering statin drugs is modulated by NO levels, stimulation of NO bioavailability is expected to affect blood lipid composition. For additional background on the interrelationship between LDL and NO, see generally:                (19) Martinez-Gonzalez, J., et al., Arterioscler. Thromb. Vasc. Biol. 21: 804-809 (2001).        
As described above, it has been known for some time that exercise can provide relief from hypertension in certain individuals. As the modulation of nitric oxide levels is part of a feedback system that responds in part to the stretching and extensibility of blood vessels of the body, it is hypothesized that exercise in general plays a role in stimulating cycles of NO release, and effectively providing some of the benefits of statin drugs, including improvement in endothelial function, increased nitric oxide bioavailability, anti-oxidant effects, anti-inflammatory protection, and stabilization of atherosclerotic plaques. Notwithstanding the effects of the modulation of NO bioavailability, exercise is known to modulate blood cholesterol and blood lipid composition.
There is widespread discourse on the relative benefits of particular forms of exercise. There is an ongoing need for patients suffering from hypertension, hypercholesteremia, atherosclerosis, and other cardiovascular and cardiopulmonary diseases to obtain the maximum benefit from the exercise utilized. Patients who are suffering from severe cardiovascular disease may be unable to engage in intense exercise, and many patients may be unable to engage in other forms of exercise due to limitations in time or facility availability. The invention disclosed herein provides for a device, system and method of exercise that can be optimized to provide an improved benefit to the patient in stimulating endothelial function, overall blood vessel health, and cardiovascular benefit while at the same time limiting the dangerous side effects of intensive exercise.
In contrast to the approach of Wiley, earlier subjects or trainees undergoing isometric exercise stressed the involved musculature to their full or maximum capability (publication (11)) or at some submaximal force as long as it could be sustained, in either case only terminating with the onset of unendurable fatigue. Such approaches often have incurred somewhat deleterious results as evidenced by the injuries sustained in consequence of improper weightlifting procedures. Weightlifting procedures or endeavors exhibit a significant isometric factor. See generally:                (20) Lind A R. “Cardiovascular Responses to Static Exercise”(Isometrics, Anyone?) Circulation 1970:41(2):173-176.        (21) Mitchell J H, Wildenthal K. “Static (Isometric) Exercise and the Heart: Physiological and Clinical Considerations”. Ann Rev Med 1974;25:369-81.        
The diagnosis of patient hand-arm strength using isometric-based testing has been employed by physiologists, physical therapists and medical personnel for over three decades. These procedures function to evaluate hand-arm trauma or dysfunction and involve the patient use of a handgrip-based dynamometer. The dynamometer is grasped by the patient and squeezed to a maximum capability under the verbal instruction of an attending therapist or diagnostician. The hand dynamometer most widely used for these evaluations incorporates a grip serving to apply force through closed circuit hydraulics to a force readout provided by an analog meter facing outwardly so as to be practitioner readable. Adjustment of the size of the grip of the dynamometer is provided by inward or outward positioning of a forwardly disposed grip component. The dynamometers currently are marketed under the trade designation: “Jamar Hydraulic Hand Dynamometer” by Sammons Preston of Bolingbrook, Ill. An extended history of use of these dynamometers has resulted in what may be deemed a “standardization” of testing protocols. For instance, three of the above-noted grip length adjustments are employed in a standardized approach and verbal instructions on the part of the testing attendant, as well as the treatment of force data read from the analog meter are now matters of accepted protocol. In the latter regard, multiple maximum strength values are recorded whereupon average strengths, standard deviations and coefficients of variation are computed by the practitioner. In one test, the instrument is alternately passed between the patient's right and left hands to derive a maximum strength output reading each 1.5 seconds or 2.5 seconds. Reading and hand recording strength values for such protocols has remained problematic. The protocols, for example, have been the subject of recommendations by the American Society of Hand Therapist (ASHT) and have been discussed in a variety of publications including the following:                (22) Mathiowetz V., Federman S., Wiemer D. “Grip and Pinch Strength: Norms for 6 to 19 Year Olds.” The American Journal of Occupational Therapy 40:705-11, 1986.        (23) Mathiowetz V., Donohoe L., Renells C. “Effect of Elbow Position on Grip and Key Pinch Strength.” The Journal of Hand Surgery 10A;694-7, 1985.        (24) Mathiowetz V., Dove M., Kashman N., Rogers S., Volland G., Weber K. “Grip and Pinch Strength: Normative Data for Adults.” Arch Phys Med Rehabilitation 66:69-72, 1985.        (25) Mathiowetz V., Volland G., Kashman N., “Reliability and Validity of Grip and Pinch Strength Evaluations.” The Journal of Hand Surgery 9A:22-6, 1984.        
In about 1998, the above-noted Wiley protocols as described in connection with publication (12) above were incorporated in a compact, lightweight isometric device. Described in detail in U.S. Pat. No. 5,904,639 entitled “Apparatus, System, and Method for Carrying Out Protocol-Based Isometric Exercise Regimens” by Smyser, et al., the hand-held dynamometer has a hand grip which incorporates a load cell assembly. Extending from the hand grip is a liquid crystal display and two user actuated control switches or switch buttons. The display is mounted in sloping fashion with respect to the grip such that the user can observe important visual cues or prompts while carrying out a controlled exercise regimen specifically structured in terms of force values and timing in accordance with the Wiley protocols. This device is therapeutic as opposed to diagnostic in nature and is microprocessor driven with archival memory. External communication with the battery powered instrument is made available through a communications port such that the device may be configured by programming and, additional data, such as blood pressure values and the like may be inserted into its memory from an external device. Visual and audible cueing not only guides the user through a multi-step protocol but also aids the user in maintaining pre-computed target level grip compression levels.
Of course, it will be beneficial to incorporate improved diagnostic features for hand-arm evaluation techniques with therapist or practitioner designed therapeutic protocols specifically tailored to the condition of a given patient and which provide a control over such therapies clearly establishing such therapies as beneficial to strength development and recovery. One particular diagnostic and therapeutic feature that would be beneficial to incorporate is protocol that modulates wall shear stress of blood vessels so as to increase the bioavailability of nitric oxide and foster a reduction in total peripheral resistance in blood vessels and a reduction in mean arterial pressure, along with the other physiologic benefits associated with stimulation of NO signaling pathways, including reduction in LDL and cholesterol concentrations and an increase. in arterial flexibility.